Controlling drug release from non-aqueous environments: Moderating delivery from ocular silicone oil drug reservoirs to combat proliferative vitreoretinopathy

Abstract

In a number of cases of retinal detachment, treatment may require the removal of the vitreous humour within the eye and replacement with silicone oil to aid healing of the retina. The insertion of silicone oil offers the opportunity to also deliver drugs to the inside of the eye; however, drug solubility in silicone oil is poor and release from this hydrophobic drug reservoir is not readily controlled. Here, we have designed a range of statistical graft copolymers that incorporate dimethylsiloxane and ethylene glycol repeat units within the side chains, allowing short chains of oligo(ethylene glycol) to be solubilised within silicone oil and provide hydrogen bond acceptor sites to interact with acid functional drug molecules. Our hypothesis included the potential for such interactions to be able to delay/control drug release and for polymer architecture and composition to play a role in the silicone oil miscibility of the targeted polymers. This strategy has been successfully demonstrated using both ibuprofen and all-trans retinoic acid; drugs with anti-inflammatory and anti-proliferation activity. After the copolymers were shown to be non-toxic to retinal pigment epithelial cells, studies of drug release using radiochemical approaches showed that the presence of 10v/v% of a linear graft copolymer could extend ibuprofen release over three-fold (from 3days to >9days) whilst the release of all-trans retinoic from the silicone oil phase was extended to >72days. These timescales are highly clinically relevant showing the potential to tune drug delivery during the healing process and offer an efficient means to improve patient outcomes.

Amphiphilic additives in silicone oil tamponade and emulsification: an eye‐on‐a‐chip study

“…Recently, by chemically modifying the side branches of the polymer chains of SiO, solubility of lipophilic drugs, such as ibuprofen and all‐trans retinoic acid, are significantly enhanced (Cauldbeck et al. , ). This inspires the opportunity of using SiO as an effective reservoir to deliver and sustained release ophthalmic drugs into the eye.…”

“…The importance of this study is that previous studies on drug release in SiO did not take into account emulsification of SiO (Cauldbeck et al. , ). The pharmacokinetics of drugs is likely to be very different if SiO emulsifies as the total surface area of SiO changes (Lallemand et al.…”

“…Adding high-density materials yields SiO blends that possess a higher density than water to tackle inferior retinal diseases (Joussen et al 2007). Recently, by chemically modifying the side branches of the polymer chains of SiO, solubility of lipophilic drugs, such as ibuprofen and all-trans retinoic acid, are significantly enhanced (Cauldbeck et al 2016(Cauldbeck et al , 2018. This inspires the opportunity of using SiO as an effective reservoir to deliver and sustained release ophthalmic drugs into the eye.…”

“…To understand the role of amphiphilic additives in SiO on emulsification, we use a variety of SiO-soluble surfactants to test our hypothesis in this study. The importance of this study is that previous studies on drug release in SiO did not take into account emulsification of SiO (Cauldbeck et al 2016(Cauldbeck et al , 2018. The pharmacokinetics of drugs is likely to be very different if SiO emulsifies as the total surface area of SiO changes (Lallemand et al 2012).…”

Centrifugal Lithography: Self‐Shaping of Polymer Microstructures Encapsulating Biopharmaceutics by Centrifuging Polymer Drops

“…Polymeric microstructures containing biological materials have attracted attention for various biomedical applications, such as scaffolds for cell proliferation and drug‐eluting reservoirs for controlled release . Recently, dissolving microneedles (DMNs), which are implantable microscale‐polymeric needles that release biopharmaceutics from their dissolving polymer matrix into the skin, have been investigated as an alternative biomedical delivery system to hypodermic injection owing to their minimal invasiveness and reduced side effects compared with traditional hypodermic injection .…”